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Category: genetics

Size-shifting nanoparticles successfully deliver mRNA medicine to the pancreas

In recent years, mRNA in lipid nanoparticles (mRNA–LNPs) has emerged as a promising strategy for treating numerous conditions, including COVID-19, various cancers and chronic genetic disorders. To date, this technology has not been successfully used for pancreatic diseases, but that could be about to change. In a paper published in Nature, scientists from China report the development of a new lipid nanoparticle drug-delivery system specifically designed for the pancreas.

Lipid nanoparticles are a special class of fat-based carriers that encapsulate and deliver nucleic acids such as messenger RNA into cells. Among the reasons they have not worked for the pancreas until now is that most LNPs naturally accumulate in the liver and spleen. That means the therapeutic molecules they carry can’t accumulate to high enough levels to be beneficial.

However, the research team realized that while the liver and spleen are wrapped in a dense, protective outer layer called a capsule, the pancreas is only covered by a thin layer of connective tissue. They wondered if these organ capsules act as a biological filter. If so, they could perhaps design nanoparticles large enough to be physically blocked by the walls of the spleen and liver, leaving the pancreas as the only place to go. They named this discovery the capsule-filter-mediated pancreatic-targeted (CAMP) mechanism.

Cellular Reprogramming: The Expert Roundup

Cellular reprogramming is one of the technologies most associated with longevity. The field was created in 2006, when Shinya Yamanaka showed that a cocktail of four transcription factors, commonly known as OSKM, can cause de-differentiation and massive rejuvenation of a cell, creating an iPSC (induced pluripotent stem cell). About a decade later, partial reprogramming was demonstrated in vivo, where a more subtle application of the factors led to rejuvenation without compromising the cell’s identity.

Today, this field is maturing quickly, with its first clinical trials just around the corner. Academic teams and companies are working on dozens of directions and applications. We asked four experts, all involved in reprogramming-related biotech companies, to talk about their companies’ approaches and the opportunities and bottlenecks that the field faces and to offer predictions for the near and not-so-near future.

What I find most compelling about cellular reprogramming is that it revealed aging to be, at least in part, an actively maintained biological state rather than irreversible accumulation of damage. The discovery that somatic cells retain a latent capacity to reset their epigenetic and functional identity fundamentally changed how we think about cellular plasticity, identity, and time.

Rejuvenation And Dramatic Lifespan Extension Is Here!

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A Developmentally Informed Study of Sleep and Circadian Polygenic Scores in Adolescence

Adult sleep GWAS-derived polygenic scores demonstrated comparable associations with corresponding sleep phenotypes in Adolescents, suggesting genetic influences on sleep persist across developmental stages.

Question Do genetic variants that are associated with adult sleep/circadian phenotypes influence sleep phenotypes in adolescents?

Findings In a population-based birth cohort study (N = 3903), genetic influences on all adult sleep phenotypes (sleep duration, insomnia, daytime sleepiness, napping, and chronotype as indexed by polygenic scores derived from adult genome-wide association studies) were associated with their corresponding sleep/circadian phenotypes in adolescents aged 15 years.

Meaning Genetic variants identified in adult genome-wide association studies may also be relevant to a variety of sleep phenotypes in adolescence, suggesting that these variants index sleep phenotypes during a key developmental stage in which sleep disturbances typically emerge.

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Cancer development results from the selection of cells with mutation(s) that provide survival and proliferative advantages. Normal barriers to proliferation are overcome as clones adapt to an ever changing hostile microenvironment, where low oxygen tension, low glucose levels, and an acidic extracellular pH (all of which increase genetic instability) are found. The hypoxia inducible factors, HIF-1 and HIF-2, are upregulated in response to these conditions. This could occur by constitutive activation of PI3K signaling or inactivating mutations in, for example, the von Hippel–Lindau tumor suppressor, VHL [35-37], which normally deacetylates HIF-1α, leading to HIF-1α polyubiquitination and proteasomal degradation [38]. HIFs trans activate genes mediating proliferation, angiogenesis, intermediate metabolism (glycolysis) and pH regulation, which promote tumor development [39].

HIF-1α stimulates production of growth factors, such as transforming growth factor β (TGF-β), insulin-like growth factor 2, interleukin-6 (IL-6), interleukin-8, macrophage migration inhibitory factor (MIF), and growth factor receptors, such as the epidermal growth factor receptor (EGFR), resulting in continuous proliferative signaling. In the hypoxic environment, constitutive activation of these signaling pathways (e.g., Ras [1] and PI3K [2]) stabilizes HIF-1 and may result in “oncogene addiction” that persists through the transition from adenoma to carcinoma. In the case of PI3K, constitutive activation may result from the appearance of mutations in tumor suppressor genes (e.g., the phosphatase and tensin homolog [PTEN]), from activating mutations in the PI3K complex itself, or from aberrant signaling in receptor tyrosine kinases [40].

Interplay between cancer cell lipotypes and disease states

Lipid metabolism in cancer.

Cancer cells exhibit distinct lipotypes to sustain functional states crucial for tumorigenesis.

Various lipid metabolism components like biosynthesis, uptake, storage, and degradation of lipids contribute to cancer cell fitness.

Cancer cells dynamically transition across lipotypes under microenvironmental stress.

Targeting essential nodes in lipid metabolism may offer novel cancer therapeutics. sciencenewshighlights ScienceMission https://sciencemission.com/cancer-cell-lipotypes

While the initial transformation of cancer cells is driven by genetic alterations, tumor cell behaviors and functional states are dynamically regulated by cell-intrinsic factors including proteins, metabolites and lipids, and extrinsic microenvironmental factors. Emerging multi-omics technologies highlighted that cancer cells exhibit distinct lipidome compositions and employ specific lipid metabolic circuits for chemical conversions – collectively defined as ‘lipotypes’. We review the interplay between cancer lipotypes and cellular states, focusing on interpreting how being at different positions along the spectra of representative lipid metabolic axes influences cancerous traits. We aim to instill a system biology perspective to integrate ‘lipotypes’ into the established ‘genotype–phenotype’ framework in cancer.

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Inositol Requiring Enzyme 1α Mediates Hypertension and Vascular Remodeling

A single genetic “switch” may be the secret to how the body’s cleanup crew grows up and keeps our organs running smoothly.

Scientists at the University of Liège have identified a crucial genetic regulator that allows macrophages to fully mature and help maintain healthy organs. This regulator, known as MafB, acts as a “molecular switch” that turns specific genes on or off at the right time and in the right cells.

By carefully controlling this genetic activity, MafB enables the development of macrophages that defend the body and support normal organ function. When MafB is missing, macrophages do not work as they should and lose their ability to carry out their protective duties.

Promoters and enhancers: Tool catches gene-controlling DNA sequences doing each other’s jobs

Researchers at the Weill Institute for Cell and Molecular Biology have uncovered new evidence that two major types of gene-controlling DNA sequences, promoters and enhancers, operate with a shared logic and often perform the same jobs. The finding, made possible through a high-throughput assay they developed called QUASARR-seq, could reshape how scientists design gene therapies, interpret disease-related mutations, and understand cancer genetics.

New research from the lab of Haiyuan Yu, Tisch University Professor of Computational Biology at Cornell University’s College of Agriculture and Life Sciences (CALS) and faculty at the Weill Institute, reveals that drawing a distinction between the two classes gene controllers may be too black and white—they seem to respond to the same biological rules and act in concert.

In a study published in Nature Communications on Jan. 30 and led by Mauricio Paramo, a graduate student at the Weill Institute, the team developed a technology capable of measuring an element’s promoter and enhancer activity simultaneously, in close collaboration with the lab of John Lis, Barbara McClintock Professor of Molecular Biology & Genetics. This is significant because, until now, most technologies could measure only one function at a time, leaving open the question of whether—and how—the two activities interact inside the same DNA sequence.

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